Higher order aberrations,refractive error development and myopia control: a review

Evidence from animal and human studies suggests that ocular growth is influenced by visual experience. Reduced retinal image quality and imposed optical defocus result in predictable changes in axial eye growth. Higher order aberrations are optical imperfections of the eye that alter retinal image quality despite optimal correction of spherical defocus and astigmatism. Since higher order aberrations reduce retinal image quality and produce variations in optical vergence across the entrance pupil of the eye, they may provide optical signals that contribute to the regulation and modulation of eye growth and refractive error development. The magnitude and type of higher order aberrations vary with age, refractive error, and during near work and accommodation. Furthermore, distinctive changes in higher order aberrations occur with various myopia control treatments, including atropine, near addition spectacle lenses, orthokeratology and soft multifocal and dual-focus contact lenses. Several plausible mechanisms have been proposed by which higher order aberrations may influence axial eye growth, the development of refractive error, and the treatment effect of myopia control interventions. Future studies of higher order aberrations, particularly during childhood, accommodation, and treatment with myopia control interventions are required to further our understanding of their potential role in refractive error development and eye growth.     

Optical mechanisms regulating emmetropisation and refractive errors: evidence from animal models

Our current understanding of emmetropisation and myopia development has evolved from decades of work in various animal models, including chicks, non-human primates, tree shrews, guinea pigs, and mice. Extensive research on optical, biochemical, and environmental mechanisms contributing to refractive error development in animal models has provided insights into eye growth in humans. Importantly, animal models have taught us that eye growth is locally controlled within the eye, and can be influenced by the visual environment. This review will focus on information gained from animal studies regarding the role of optical mechanisms in guiding eye growth, and how these investigations have inspired studies in humans. We will first discuss how researchers came to understand that emmetropisation is guided by visual feedback, and how this can be manipulated by form-deprivation and lens-induced defocus to induce refractive errors in animal models. We will then discuss various aspects of accommodation that have been implicated in refractive error development, including accommodative microfluctuations and accommodative lag. Next, the impact of higher order aberrations and peripheral defocus will be discussed. Lastly, recent evidence suggesting that the spectral and temporal properties of light influence eye growth, and how this might be leveraged to treat myopia in children, will be presented. Taken together, these findings from animal models have significantly advanced our knowledge about the optical mechanisms contributing to eye growth in humans, and will continue to contribute to the development of novel and effective treatment options for slowing myopia progression in children.     

Effects of chronic optical defocus on the kitten's refractive status

Lid closure initiated early in life produces axial myopia in a variety of species. However, it is currently not known what aspects of the anomalous visual experience associated with lid closure disrupt the emmetropization process and cause abnormal ocular axial elongation. This study was designed to determine if a degradation in the quality of the spatial characteristics of the retinal image was sufficient to produce an experimental myopia. Optical rearing procedures were employed to defocus one eye of developing kittens, and retinoscopic and ultrasonic procedures were used to evaluate the effects of chronic optical defocus on the kitten's refractive status. Different defocusing lens designs and rearing protocols were included to evaluate variables that may have confounded previous investigations. The major finding is that early chronic optical defocus results in axial myopia. The prevalence and magnitude of the induced refractive errors were dependent on the magnitude of optical defocus, but they were not affected by the sign or form of the defocusing lens. The results demonstrated that the potential for a clear retinal image is important for regulating normal ocular growth and maintaining a near emmetropic refractive status.     

光学离焦技术控制近视的研究进展

近视是一种常见的眼病,近年来,近视的发生率在全球范围内呈逐年上升趋势,高度近视会增加视力丧失的风险,近视的并发症可引起巨大的经济和社会效益损失。因此,实施控制近视的有效措施至关重要且迫在眉睫。人们对近视的发病机制研究表明,周围远视离焦引起眼球轴向伸长不受控制可能是近视发展的机制之一,由此引申的各种光学策略尤其是光学离焦技术控制近视日益成为近视管理主流临床实践的一部分。本文从光学离焦控制近视的原理、离焦性近视动物实验研究、不同光学离焦技术控制近视的最新临床应用等方面进行综述,总结了使用渐进多焦眼镜、周边离焦框架眼镜、多点近视离焦框架眼镜、角膜塑形镜及多焦点软性角膜接触镜控制近视的临床研究结果,拟为延缓近视进展的治疗方案设计提供新的选择。     

Compensation for experimentally induced hyperopic anisometropia in adolescent monkeys

PURPOSE: Early in life, the optical demand associated with the eye's effective refractive state regulates emmetropization in many species, including primates. However, the potential role of optical demand and/or defocus in the genesis of common refractive errors, like myopia, that normally develop much later in life is not known. The purpose of this study was to determine whether chronic optical defocus alters refractive development in monkeys at ages corresponding to when myopia typically develops in children. METHODS: A hyperopic anisometropia was produced in seven adolescent rhesus monkeys by photorefractive keratectomy (PRK) with an excimer laser. Standard treatment algorithms for correcting myopia in humans were used to selectively flatten the central cornea of one eye thereby producing relative hyperopic refractive errors in the treated eyes. The laser ablation zones were 5.0 mm in diameter and centered on the monkeys' pupils. The laser procedures were performed when the monkeys were 2 to 2.5 years old, which corresponded to onset ages between approximately 8 and 10 human years. The ocular effects of the induced anisometropia were assessed by corneal topography, retinoscopy, and A-scan ultrasonography. RESULTS: By approximately 30 days after PRK, the experimentally induced refractive errors had stabilized and the treated eyes were between +0.75 and +2.25 D more hyperopic than their fellow eyes. Subsequently, over the next 300 to 400 days, six of the seven monkeys showed systematic reductions in the degree of anisometropia. Although some regression in corneal power occurred, the compensating refractive changes were primarily due to relative interocular differences in vitreous chamber growth. CONCLUSIONS: Vision-dependent mechanisms that are sensitive to refractive error are still active in adolescent primates and probably play a role in maintaining stable refractive errors in the two eyes. Consequently, conditions that result in consistent hyperopic defocus could potentially contribute to the development of juvenile onset myopia in children.     

Animal models in myopia research

Our current understanding of the development of refractive errors, in particular myopia, would be substantially limited had Wiesel and Raviola not discovered by accident that monkeys develop axial myopia as a result of deprivation of form vision. Similarly, if Josh Wallman and colleagues had not found that simple plastic goggles attached to the chicken eye generate large amounts of myopia, the chicken model would perhaps not have become such an important animal model. Contrary to previous assumptions about the mechanisms of myopia, these animal models suggested that eye growth is visually controlled locally by the retina, that an afferent connection to the brain is not essential and that emmetropisation uses more sophisticated cues than just the magnitude of retinal blur. While animal models have shown that the retina can determine the sign of defocus, the underlying mechanism is still not entirely clear. Animal models have also provided knowledge about the biochemical nature of the signal cascade converting the output of retinal image processing to changes in choroidal thickness and scleral growth; however, a critical question was, and still is, can the results from animal models be applied to myopia in children? While the basic findings from chickens appear applicable to monkeys, some fundamental questions remain. If eye growth is guided by visual feedback, why is myopic development not self‐limiting? Why does undercorrection not arrest myopic progression even though positive lenses induce myopic defocus, which leads to the development of hyperopia in emmetropic animals? Why do some spectacle or contact lens designs reduce myopic progression and others not? It appears that some major differences exist between animals reared with imposed defocus and children treated with various optical corrections, although without the basic knowledge obtained from animal models, we would be lost in an abundance of untestable hypotheses concerning human myopia.     

Optical changes and visual performance with orthokeratology

Orthokeratology has undergone drastic changes since first described in the early 1960s. The original orthokeratology procedure involved a series of lenses to flatten the central cornea and was plagued by variable results. The introduction of highly oxygen-permeable lens materials that can be worn overnight, corneal topography, and reverse-geometry lens designs revolutionised this procedure. Modern overnight orthokeratology causes rapid, reliable, and reversible reductions in refractive error. With modern designs, patients can wear lenses overnight, remove them in the morning, and see clearly throughout the day without the need for daytime refractive correction. Modern reverse-geometry lens designs cause central corneal flattening and mid-peripheral corneal steepening that provides clear foveal vision while simultaneously causing a myopic shift in peripheral retinal defocus. The peripheral myopic retinal defocus caused by orthokeratology is hypothesised to be responsible for reductions in myopia progression in children fitted with these lenses. This paper reviews the changes in orthokeratology lens design that led to the reverse-geometry orthokeratology lenses that are used today and the optical changes these lenses produce. The optical changes reviewed include changes in refractive error and their time course, high- and low-contrast visual acuity changes, changes in higher-order aberrations and visual quality metrics, changes in accommodation, and changes in peripheral defocus caused by orthokeratology. The use of orthokeratology for myopia control in children is also reviewed, as are hypothesised connections between orthokeratology-induced myopic peripheral defocus and slowed myopia progression in children, and safety and complications associated with lens wear. A better understanding of the ocular and optical changes that occur with orthokeratology will be beneficial to both clinicians and patients in making informed decisions regarding the utilisation of orthokeratology. Future research directions with this lens modality are also discussed.     

Practical applications to modify and control the development of ametropia

For many individuals, the developmental trend of lessening hyperopia from birth continues past emmetropia towards myopia during childhood. The global pattern for prevalence of refractive errors indicates that the prevalence of hyperopia is low; in contrast, the burden of myopia is on the rise because of rising prevalence and magnitude of myopia. This review highlights the need to lessen the global burden of myopia by intervening with the development and/or slowing the progression of myopia. Further, outcomes from human clinical trials of pharmaceutical, optical, and environmental approaches to control myopia will be summarised. Pharmaceutical treatments are effective in controlling eye growth but are associated with deleterious side effects. Optical strategies that induce myopic defocus at the retina such as peripheral defocus reducing lenses, simultaneous defocus lenses, bifocals, and orthokeratology as well as environmental influences such as increased outdoor activity show promise and provide a substantially risk-free environment in which to control eye growth.     

周边视网膜相对屈光度与近视进展的关系

在正视眼或者低度远视眼中,周边视网膜呈相对远视屈光状态者比周边视网膜呈相对近视屈光状态者更容易发展为近视眼.正视眼周边视网膜呈轻度相对近视屈光状态,未矫正的远视眼周边视网膜呈稍大程度的相对近视屈光状态,未矫正的近视眼周边视网膜呈轻度相对远视屈光状态或比正视眼程度轻的相对近视状态.这两种观点已经被学者广泛接受.动物实验也证明异常视觉信号不仅能引起中央视网膜屈光不正,也能改变眼球后极部眼球形态和周边视网膜相对屈光不正的类型,并且黄斑切除并不影响正视化过程.相反,周边视网膜能单独调控眼球正视化过程并能对异常视觉信号起作用进而发展为各种屈光不正.临床研究表明,矫正视网膜周边远视性离焦的框架镜片对近视眼进展能起到一定的控制作用.虽然,周边视网膜远视性离焦是否促进近视进展的确切原因还不能肯定,但目前的研究倾向于认为两者之间可能有某种关系.     

Simultaneous defocus integration during refractive development

PURPOSE: To determine the effects of simultaneously presented myopic and hyperopic defocus on the refractive development of chicks. METHODS: A novel form of dual-power lens was designed. Normal chicks 7 to 8 days of age were fitted with a dual-power lens over one eye and a plano lens over the fellow (control) eye. Dual-power lenses of +20/-10, +10/-10, +5/-10, and plano/-10-D were tested, along with +10/-10-D lenses having differing ratios (50:50, 33:67, and 25:75) of surface area devoted to each power. Ocular refraction and axial ocular component dimensions were assessed after 6 days of lens wear, by retinoscopy and high-frequency ultrasound, respectively. In a separate experiment designed to test the effect of dual-power lens wear on the refractive development of myopic eyes, chicks were fitted with a dual-power +10/-10-D lens for 6 days, after myopia had been induced by 6 days of -10-D lens wear. RESULTS: For each of the dual-power lenses tested, the refractive end point of the treated eye was found to lie between the two optical powers of the lens (but with the response weighted in favor of the effect of myopic defocus). Refractive development appeared to be modulated by the sign, dioptric magnitude, and relative contribution (relative contrast) of the imposed optical defocuses through an integrative mechanism. Chicks with myopia induced by -10-D lens wear recovered when treated with a +10/-10-D dual-power lens. CONCLUSIONS: The chick retina can discern both the sign and the magnitude of optical defocus. Chick eyes were able to integrate blur cues from simultaneously presented images focused either side of the photoreceptors and to modulate their refractive development accordingly. This implies that the complex nature of defocus in the visual environment may play a critical role in the pathogenesis of myopia. The results suggest a rational method for arresting or reversing the development of myopia, which may be useful in the treatment of human myopia if the primate retina is also capable of responding to simultaneously presented opposing defocus cues.     

The complex interactions of retinal,optical and environmental factors in myopia aetiology

Myopia is the commonest ocular abnormality but as a research topic remains at the margins of mainstream ophthalmology. The concept that most myopes fall into the category of ‘physiological myopia’ undoubtedly contributes to this position. Yet detailed analysis of epidemiological data linking myopia with a range of ocular pathologies from glaucoma to retinal detachment demonstrates statistically significant disease association in the 0 to ?6 D range of ‘physiological myopia’. The calculated risks from myopia are comparable to those between hypertension, smoking and cardiovascular disease. In the case of myopic maculopathy and retinal detachment the risks are an order of magnitude greater. This finding highlights the potential benefits of interventions that can limit or prevent myopia progression.Our understanding of the regulatory processes that guide an eye to emmetropia and, conversely how the failure of such mechanisms can lead to refractive errors, is certainly incomplete but has grown enormously in the last few decades. Animal studies, observational clinical studies and more recently randomized clinical trials have demonstrated that the retinal image can influence the eye’s growth. To date human intervention trials in myopia progression using optical means have had limited success but have been designed on the basis of simple hypotheses regarding the amount of defocus at the fovea.Recent animal studies, backed by observational clinical studies, have revealed that the mechanisms of optically guided eye growth are influenced by the retinal image across a wide area of the retina and not solely the fovea. Such results necessitate a fundamental shift in how refractive errors are defined. In the context of understanding eye growth a single sphero-cylindrical definition of foveal refraction is insufficient. Instead refractive error must be considered across the curved surface of the retina. This carries the consequence that local retinal image defocus can only be determined once the 3D structure of the viewed scene, off axis performance of the eye and eye shape has been accurately defined. This, in turn, introduces an under-appreciated level of complexity and interaction between the environment, ocular optics and eye shape that needs to be considered when planning and interpreting the results of clinical trials on myopia prevention.     

The effect of positive lens defocus on ocular growth and emmetropization in the tree shrew

Optical defocus influences postnatal ocular development in animal models. Induced negative lens defocus results in accelerated ocular elongation and myopia. Positive lens-induced defocus findings across animal models have been inconsistent. Specifically, in the tree shrew, positive lens-induced defocus has produced equivocal results. This study evaluated the response of the tree shrew to induced positive lens defocus. One treatment group wore positive lenses binocularly, which were increased in power sequentially from +2 to +4, +6, +8, and +9.5 D over 8 weeks. Other groups wore +4, +6, and +9.5 D lenses, respectively, for 8 weeks. Animals wearing zero-powered (plano) lenses served as controls. Refractive error and ocular dimensions were measured at the start of treatment and every week thereafter. Sequentially increasing positive lens power caused a relative hyperopia of +5.6 D (p < 0.01) compared to the plano lens group (+10.9 +/- 1.8 D vs +5.3 +/- 0.5 D). Constant +4 D lens wear produced +6.9 D relative hyperopia, while +6 and +9.5 D lens wear did not induce hyperopia. Lens-induced defocus changes in refractive state were significantly correlated with vitreous chamber depth changes. The threshold for consistent responses to positive lens defocus in tree shrew was between +4 and +6 D. The results will enable targeted investigation of the efficacy of positive lens defocus in inhibiting myopic ocular growth.     

The role of the retinal pigment epithelium in eye growth regulation and myopia: a review

Myopia is increasing in prevalence world-wide, nearing epidemic proportions in some populations. This has led to expanded research efforts to understand how ocular growth and refractive errors are regulated. Eye growth is sensitive to visual experience, and is altered by both form deprivation and optical defocus. In these cases, the primary targets of growth regulation are the choroidal and scleral layers of the eye that demarcate the boundary of the posterior vitreous chamber. Of significance to this review are observations of local growth modulation that imply that the neural retina itself must be the source of growth-regulating signals. Thus the retinal pigment epithelium (RPE), interposed between the retina and the choroid, is likely to play a critical role in relaying retinal growth signals to the choroid and sclera. This review describes the ion transporters and signal receptors found in the chick RPE and their possible roles in visually driven changes in eye growth. We focus on the effects of four signaling molecules, otherwise implicated in eye growth changes (dopamine, acetylcholine, vasoactive intestinal peptide (VIP), and glucagon), on RPE physiology, including fluid transport. A model for RPE-mediated growth regulation is proposed.     

Developmental visual system anomalies and the limits of emmetropization

Optical defocus can within certain limits predictably alter ocular growth and refractive development in infant monkeys. However defocus, particularly unilateral defocus associated with anisometropia, can also promote abnormal sensory and motor development. We investigated the relationship between the effective operating range for emmetropization in infant monkeys and the refractive errors that produced amblyopia. Specifically, we examined the refractive-error histories of monkeys that did not demonstrate compensating ocular growth for imposed refractive errors and used operant psychophysical methods to measure contrast sensitivity functions for 17 infant monkeys that were reared with varying degrees of optically imposed anisometropia. Imposed anisometropias that were within the operating range of the monkey's emmetropization process were eliminated by differential interocular growth and did not produce amblyopia. On the other hand imposed anisometropias that failed to initiate compensating growth consistently produced amblyopia; the depth of the amblyopia varied directly with the magnitude of the imposed anisometropia. These results indicate that amblyopia and anisometropia are frequently associated because persistent anisometropia causes amblyopia. However, the failure of emmetropization in infants with refractive conditions that are known to promote sensory and motor anomalies indicates that factors other than optical defocus, presumably factors associated with the development of amblyopia and/or strabismus, can also influence early refractive development and in some cases cause anisometropia.     

Myopia: precedents for research in the twenty-first century

The myopic eye is generally considered to be a vulnerable eye and, at levels greater than 6 D, one that is especially susceptible to a range of ocular pathologies. There is concern therefore that the prevalence of myopia in young adolescent eyes has increased substantially over recent decades and is now approaching 10-25% and 60-80%, respectively, in industrialized societies of the West and East. Whereas it is clear that the major structural correlate of myopia is longitudinal elongation of the posterior vitreous chamber, other potential correlates include profiles of lenticular and corneal power, the relationship between longitudinal and transverse vitreous chamber dimensions and ocular volume. The most potent predictors for juvenile-onset myopia continue to be a refractive error 相似文献   

远视性光学离焦对青少年期猴眼屈光状态的影响

目的动态观察远视性光学离焦对青少年期猴眼屈光状态的影响,了解视觉反馈在相当于人类近视眼发生的关键年龄对屈光状态发育过程的调控作用。方法年龄2．0—2．5岁的健康恒河猴（相当于人类8—10岁）7只,1只眼接受准分子激光角膜屈光手术（PRK）,使术后产生1．00～2．00D远视性光学离焦;另一眼作为对照。处理前和处理后不同时间点分别用角膜地形图、睫状肌麻痹验光和A超动态观察猴眼屈光状态的变化,观察时间为3年。结果术后约30d,实验性的屈光不正度数已稳定,7只猴双眼屈光参差为0．75～2．25D,实验眼与对照眼比较处于更加远视的状态;在随后的观察期内,实验眼均表现为代偿生长的过程,玻璃体腔增长速率较对照眼快（t=3．565,P=0．0119）;在此过程中,角膜曲率也发生一定回复,但屈光参差程度的减少主要由双眼玻璃体腔增长的差异引起（r=0．74,P=0．046）。结论远视性光学离焦仍然可通过加快玻璃体腔增长速率影响青少年期灵长类动物屈光状态发育过程,因此持续性的远视性光学离焦可能对儿童近视的发生发展有潜在的影响。     

Effects of experimentally induced ametropia on the morphology and optical quality of the avian crystalline lens

PURPOSE: To examine the effects of refractive error on avian lens morphology and optical quality. METHODS: Hatchling white leghorn chicks were unilaterally goggled for 7 days with either a form-deprivation goggle (n = 12), a -10 D defocus goggle (n = 12), or a +10 D defocus goggle (n = 12) to induce myopia and hyperopia. Optical quality of lenses (focal length and focal length variability) from treated and contralateral control eyes was assessed using a scanning laser apparatus. Lens morphology was examined by light and electron microscopy. RESULTS: Although the induction of refractive errors did not significantly alter lens size, shape, paraxial focal length, or average focal length, average focal length variability increased. Lenses from eyes goggled with form-deprivation and +10 D defocus goggles demonstrated a twofold increase in average focal length variability, when compared with their contralateral controls. The morphology of the lens is not altered by these experimental manipulations. CONCLUSIONS: This study provides evidence that the refractive development of the chick lens is not independent of the refractive development of the ocular globe and that chick lenticular development is influenced by both genetics and visual experience.     

Visual field does not affect steady-state accommodative response and near-work induced transient myopia

To investigate whether or not peripheral retinal defocus contributes to the refractive development of myopia by influencing the overall accommodative function. The steady-state accommodative stimulus response curve (ASRC) and the near-work induced transient myopia (NITM) after a near visual task were compared between different visual field conditions in emmetropes (EMMs), stable myopes (SMs) and progressing myopes (PMs). Results showed that visual field had no effect on the ASRC and NITM but PMs exhibited greater NITM than EMMs and SMs. The results of this study suggest that peripheral defocus does not influence the overall accommodative system so its probable contribution to myopia development is not via the accommodative system.     

Form deprivation myopia in mature common marmosets (Callithrix jacchus)

PURPOSE: Experimental manipulations of visual experience are known to affect the growth of the eye and the development of refractive state in a variety of species including human and nonhuman primates. For example, it is well established that visual form deprivation causes elongation of the eye and myopia. The effects of such manipulations have generally been examined in neonatal or juvenile animals. Whether adolescent common marmosets (a new world primate) are susceptible to form deprivation myopia was studied. METHODS: Five adolescent marmosets were used in this study. Monocular form deprivation was induced by lid closure for 12 to 20 weeks, starting between 299 and 315 days of age. The effects of deprivation were assessed with keratometry, A-scan ultrasonography, and cycloplegic refractions. Both eyes (treated and fellow control) were measured before lid-closure, at the end of the deprivation period, and several times over the following 8 to 12 weeks. RESULTS: Adolescent marmosets are susceptible to visual form deprivation myopia. The experimental eyes showed significant axial elongation and myopia relative to the fellow control eyes. These changes were smaller, however, than those observed in younger eyes deprived for comparable periods. Like juvenile animals, the adolescent marmosets did not show recovery from myopia over the period monitored. CONCLUSIONS: The period for susceptibility to form deprivation myopia in the marmoset monkey extends beyond the early developmental period when ocular growth is rapid and emmetropization normally takes place. Visual form deprivation in adolescent marmosets with adult-sized eyes results in increased ocular growth and myopia. These data suggest that visual factors may influence the growth and refractive development of the human eye after puberty and may be involved in late-onset myopia.